Description: (Applicant's Description) The Cancer Genetics Program consists of 11 Members, representing total peer-reviewed funding of $2,514,145 in annual direct costs. During the last year, its Members were responsible for a total of 65 cancer-relevant, peer-reviewed publications 25% of which were intra- and inter-programmatic collaborations. The time is now optimal to exploit the techniques of classical and molecular genetics in the study of cancer, both for understanding the mechanistic basis of the disease and for developing therapeutic interventions. The information coming on stream from the Human Genome Project and the availability of tools for use in linkage analysis and positional cloning have facilitated the gene discovery process. This is resulting in the continuing identification of genetic abnormalities involved in the development of various types of cancer. Additionally, the ready availability of experimental methods for the genetic modification of both mouse and human cells have allowed investigators to study the significance and functional implications of these newly recognized abnormalities for the development and treatment of cancer directly in mammalian systems. Rapid progress in understanding model organisms like yeast, D. melanogaster, X laevis and C. Elegans, coupled with the realization that many molecular pathways are important regarding the development of cancer in higher species are conserved between mammalian cells and model organisms, has led to the productive introduction of studies of such organisms into cancer research. Integrated application of these different but complementary approaches to mammalian genetics will likely unify and accelerate our understanding of the interlocking disturbances in the structural and regulatory components of the genome which characterize the onset of neoplasia. Members of the Cancer Genetics program are organized into four interactive sub-programs namely, Model Systems, Mouse Genetics, Mammalian Genetics and Clinical Genetics, all working on topical problems in Cancer Genetics. The sub-programs cooperate with each other to facilitate the application of expertise in one discipline to research problems that are the focus of other disciplines. There are further collaborations between the Genetics Program and other programs at the Center and with other cancer centers across the country. Some of the more notable results of these latter interchanges are the widespread use of mouse model systems and mouse genetics facilities. They have also encouraged the development of an Experimental and Clinical Human Cancer Genetics Program that encompasses many Cancer Center Members, local medical institutions and the UC Irvine Cancer Center. The UCSD Cancer Center was selected as one of the eight centers for funding by the NCI as part of its Cancer Geneti cs Network.